How the area of ​​the brain implicated in Alzheimer’s disease may be prone to degeneration

Summary: The study reveals a new mechanism in neurites resulting from the loss of the mitochondrial enzyme GPT2 involved in the development and progression of neurodegenerative diseases.

source: Brown University

The coeruleus is among the first brain regions to degenerate in Alzheimer’s and Parkinson’s disease, as doctors and scientists know. But the reason for the weakness of this region is not understood.

As they continue their exploration of a rare neurological disorder, a team of Brown University researchers has discovered explanations that shed light on this important question.

in the magazine Neurobiology of diseaseResearchers report a new mechanism of degeneration in neurites caused by loss of the mitochondrial enzyme, GPT2, implicated in the neurological disorder the researchers are focusing on.

“These findings represent a new direction for research in this really important part of the brain,” said study author Dr. Eric Morrow, professor of biology, neuroscience, psychiatry, and human behavior at Warren Albert School of Medicine, and director of Brown University. Center for Translational Neuroscience.

The blue locus is located in the brainstem, a critical region that houses a major source of neurons, providing the neurotransmitter norepinephrine via projections throughout the brain. Morrow said norepinephrine is a common target for many diseases.

The blue locus is involved in a variety of cognitive processes such as attention, learning, mood, wakefulness, and sleep. The death of neurons in this part of the brain also leads to cognitive diseases such as Alzheimer’s disease and Parkinson’s.

In recent years, Morrow said, the blue locus has become an area of ​​widespread and intense research interest. However, his team did not originally attempt to study this part of the brain in its experiments.

“That’s one of the things that makes this discovery so exciting,” Moreau said. “This was a completely serendipitous discovery that, frankly, could have been missed. This is an example of how research focused on genetic information can teach us previously unexpected lessons about the brain.”

The team, which includes Brown neuroscience graduate student Ozan Pettas, was investigating how a specific gene mutation is implicated in a rare genetic neurological disorder called GPT2 deficiency — a genetic syndrome first reported by the Moro lab in 2016.

The gene in question is called GPT2 (Glutamate Pyruvate Transaminase 2), and it generates an enzyme vital to metabolic pathways in the mitochondria, the energy centers of cells.

After introducing the mutation in a metabolic gene into lab mice to study GPT2 deficiency, the researchers discovered that this loss of the mitochondrial enzyme caused the degeneration of the globular locus relatively early and selectively in the mouse’s life.

The GPT2 enzyme regulates neuronal growth by replenishing the tricarboxylic acid cycle intermediates and modulating amino acid metabolism.

In mice without the GPT2 enzyme, the researchers observed an early loss of neurons in the blue position, as well as other signs of degeneration, such as decreased protein synthesis and stunted cell growth.

A specific part of the work involved the electrophysiology of neurons. These experiments were conducted in the lab of co-author Julie Kaur, then at Brown and Professor of Psychiatry and Behavioral Sciences at Stanford University.

This indicates brain samples from lc
Images from the paper show signs of neurodegeneration in the localized part of the brain. This is reflected in purple neurons surrounded by active green glial cells in the animal model of GPT2 deficiency (“GPT2-null”). Credit: Brown University

“Our results suggest that altered metabolism may be the primary driving force for neurodegeneration in the blue locus,” said study lead author Pettas.

“Determining the exact causes of this degeneration may tell us about disease mechanisms in the blue locus that we can correct, or better prevent, in order to stop dementia and related behavioral conditions.

“Our findings in a mouse model of a neuro-metabolic disease open new perspectives on neurodegeneration in the blue locus and encourage further research on the metabolic susceptibility of these neurons.”

Given the focus on the blue locus in the development of drug therapies, Morrow said this discovery about the early weakness of this area of ​​the brain will interest a wide range of people in the neuroscience and neuropsychiatry community.

The hope, he added, is that these studies will eventually culminate in therapeutic targets for Alzheimer’s disease and other neurodegenerative diseases.

About this research on neurodegeneration news

author: press office
source: Brown University
Contact: Press Office – Brown University
picture: Photo credited to Brown University

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original search: open access.
Loss of the mitochondrial enzyme GPT2 causes early neurodegeneration in the blue locusBy Ozan Pettas et al. Neurobiology of disease


Summary

Loss of the mitochondrial enzyme GPT2 causes early neurodegeneration in the blue locus

Locus coeruleus (LC) is among the first brain regions to degenerate in Alzheimer’s disease and Parkinson’s disease. However, the underlying causes of LC neuron dysfunction are not well defined.

Here we report a novel mechanism for LC neuron degeneration caused by loss of the mitochondrial enzyme glutamate pyruvate transaminase 2 (GPT2). GPT2 deficiency is a newly recognized childhood neurometabolic disorder.

The GPT2 enzyme regulates cell growth by replenishing the tricarboxylic acid (TCA) cycle intermediates and modulating amino acid metabolism. in Gpt2-Null mice, we observe an early loss of tyrosine hydroxylase (TH) positive neurons in the LC and reduced soma size at postnatal day 18. Gpt2-LC null shows positive selective fluoro-jade C staining.

Neuronal loss is associated with microgliosis and prominent selectivity in LC. We note reduced noradrenergic expectations and norepinephrine levels in the hippocampus and spinal cord.

Whole cell recordings in . format Gpt2-Blank LC slides show reduced soma volume and abnormal action potential with variable release kinetics. Remarkably, we observe early decreases in S6 phosphorylation in Gpt2-Empty LC, preceded by prominent p62 assembly, increased LC3B-II to LC3B-I ratio, and neuronal loss.

These data are consistent with a possible mechanism involving a deficiency in protein synthesis and cell growth, subsequently associated with abnormal autophagy and neurodegeneration.

Compared with the few genetic animal models with LC degeneration, the loss of LC neurons in Gpt2-Developmentally null mice are the oldest. The loss of early LC neurons in a model of human neuro-metabolic disease provides important clues regarding the metabolic impairment of LC and may lead to new therapeutic targets.

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